The long-term goal of this proposal is to study the effects of early antiretroviral therapy (ART) in HIV-infected infants and the functional reconstitution/maturation of antiviral effector mechanisms of the innate/adaptive immune system to identify correlates of delayed disease progression and possible targets for immuno-therapy. Our short-term goal, specifically addressed by this 5 year proposal covering 4 years of follow-up on 120 children, is to (a) characterize and identify the innate and adaptive immunological outcomes of early 9 or 21 months of therapy in infants infected with HIV at birth and (b) correlate outcomes to clinical progression within a period of 2-3 years of follow-up after stopping therapy. This proposal represents an immunology sub-study to a parent NlH-funded clinical trial of 375 children with perinatal HIV infection in South Africa designed to compare the efficacy, toxicity and tolerability of early ART for 9 or 21 months started in <3 month-old infected infants when compared to an infant cohort left untreated until disease progression (<20 CD4%). The parent trial with an anticipated start date of August 2004 will determine if an early and limited ART intervention before disease progression, potentially applicable to a broader cohort of infants, can reduce onset of early death and extend subsequent time to disease progression once off therapy. Based on the clinical design of the parent study including three treatment arms (9 months of ART: i.e., stop ART at age of 1, 21 months of ART: i.e., stop ART at age of 2, and no ART) with ART initiated (or reinitiated) in all once CD4% drops below 20%, the primary hypothesis for the proposed immunology sub-study is that >9 months of ART initiated by three months of age will have a significant impact on the maturation and development of antiviral effector mechanisms (development and retention of plasmacytoid CD123+ dendritic cell, CD56+ Natural Killer cells and CD4+/CD8+ proliferative antiviral responses) that will be positively associated with a delay of disease progression. We will test our hypothesis in a longitudinal study of 40 children per parent-trial arm (120 total) by quantifying the functional presence and association with disease progression of (a) frequencies of circulating dendritic cell, NK and T cell subsets, (b) proliferative/cytokine responses against consensus HIV-1 clade C Gag in CD4 and CD8 T-cell subsets, and (c) proliferative/cytokine responses against autologous viral sequences. This proposal represents a unique opportunity to characterize immune correlates of early treatment in HIV-infected infants in relation to disease progression by combining a recently NIH-funded pediatric study in South Africa with our >40 months experience studying adaptive/innate immune outcomes in HIV-1 infected children using limited numbers of cells. This study represents an international collaboration between The Wistar Institute, The University of Witswatersrand, the HIV perinatal unit of the Chris Hani-Baragwanath Hospital, Tygerberg Children's Hospital, the South African National Institute for Communicable Diseases, and the University of Pennsylvania.